Epigenetic drugs: The promise of future precise cancer treatments

Brenda Lau, 02 May 2017

Epigenetic drugs could present a viable option, especially for problems such as cancer resistance to treatments.

Precision medicine has promised a revolutionary approach to deliver care that is more life-saving and cost-effective compared to conventional treatments. Former US president Barack Obama even launched the Precision Medicine Intitiative in hopes of advancing biomedical discoveries and arm physicians with knowledge to select the best treatments for each patient.

The best example of how transformative precision medicine is often reflected in the story of the cancer drug Gleevec (imatinib) that has made chronic myeloid leukaemia (CML) a rare, fatal blood cancer, treatable since 2001.

There are many other drugs that are based on the concept of precision medicine, however cancer care is where precision medicine is often hailed.

Yet today, "the majority of cancers are [still] treated with chemotherapy that lacks specificity to the cancer," says Justin Bekelman, a professor of radiation oncology, and medical ethics and health policy at the University of Pennsylvania.

The promise of precision oncology, he says, is "to create a future — as many have imagined — where treatments are highly specific, minimally toxic and dramatically effective. And the question is whether that’s really promise, or hype.”

So why aren't there more Gleevecs? Why hasn't precision medicine fulfilled its promise to control every patient's cancer yet?

Cancer may be too complex for precision medicine

The challenge lies in the nature of cancer tumours themselves, says Steven Joffe, a professor of paediatrics, medical ethics and health policy at the University of Pennsylvania.

For CML, there was only one genetic change but for most cancers, such as a certain type of lung cancer, there are four or five changes. Some tumours contain a network of cells that have different genetic changes. Biopsies of one tumour might not reveal genetic changes of another tumour.

"Even though the promise of precision cancer is so appealing, some argue that cancers are too complex" with countless mutations, says Bekelman.

"Cancer is smart," Joffe says. Much like antibiotic-resistant bacteria, cancer cells can develop resistance as well. So while 99.99% of cancer cells in a patient are effectively treated by a particular drug, the remaining 0.01% might possess or acquire a mutation that makes them resistant. As they survive and grow, the original medication no longer works.

Shifting the drug target to epigenes

Others such as Fabian Filipp, assistant professor of Systems Biology and Cancer Metabolism at the University of California Merced, suggest that epigenetics also play an important role as a gene responds differently to the varying chemical environments.

Filipp and his colleagues have discovered an epigenetic factor called Jumonji, which is overabundant in cancer cells, affecting how the entire network of cancer genes behave and takes on the role of an epigenetic master regulator of cancer genes, promoting uncontrollable cell growth. It also collaborates with hormone-dependent regulators that are responsible for treatment-resistant cancers.

So it makes sense to make epigenetic regulators like Jumonji into a drug target. But it is easier said than done.

Epigenomics does have a lot of promise for cancer treatments, Filipp says, but there are many basic questions to answer first.

What does the epigenome of a healthy person look? How does it differ from a sick person's? And how does the epigenome change as a person ages? These questions could be addressed by personalised epigenomics, which attempts to divulge some useful information out of a comprehensive picture of a person's epigenome.

Epigenetic drugs can offer hope

But there is another problem: the epigenome is highly dynamic. Epigenomic regulators are constantly at work, removing or adding chemical marks allowing for transient gene readouts, then blocking it within the next minute. So personalised epigenomic tests are still a farfetched idea.

While it is still an open debate about whether epigenetics is on the good or on the bad side of cancer, drugs targeting the epigenomic machinery is a viable direction of clinical research, Filipp says.

Currently, most clinical epigenetic research questions address which drug molecules modify the epigenome and which specifically kill cancer cells.

A better understanding of epigenetic regulations is also needed to better design drugs that counter-regulate unlimited growth of cells. Researchers have made some breakthroughs, such as the identification of a genetic mutation in an epigenetic player for the development of melanomas.

Epigenetic drugs already exist in laboratory studies, with positive results of stopping the ability of cancer cells to evade the immune system and making tumours vulnerable.

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